(1) Field of the Invention
The present invention relates to anthraquinones which are antihelminthic and in particular, are useful in compositions for inhibiting schistosoma sp. in vitro or in vivo. The preferred anthraquinones have the formula:
wherein R1, R2, R3, and R4 are each hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkene, substituted alkene, alkyne, aryl, substituted aryl, cyclic, substituted cyclic, acid group, carbohydrate, or combination thereof, R is a group containing 1 to 12 carbons such as methyl, alkyl, substituted alkyl, aldehyde, hydroxy, hydroxymethyl, acid group, carbohydrate, or combination thereof, and the halogen is I, F, Br, or Cl. In a particular embodiment, the anthraquinones have the formula
wherein R is a group containing 1 to 12 carbons such as methyl, alkyl, substituted alkyl, aldehyde, hydroxy, hydroxymethyl, acid group, carbohydrate, and combinations thereof.
(2) Description of Related Art
Schistosomasis is a disease caused by parasitic digenetic trematodes of the genus Schistosoma that afflicts at least 200 million people worldwide with another 600 million at risk (Chitsula et al., Acta Trop. 77: 41–51 (2000)). Chronic Schistosoma infection can lead to the development of a variety of conditions including diarrhea, hepatic fibrosis and portal hypertension, central nervous system disease, embolisms of the pulmonary arterioles, and hematuria. While a large number of schistosomes are known, only five appear to be primarily responsible for human infections including Schistosoma mansoni, Schistosoma japonicum, Schistosoma mekongi, Schistosoma intercalatum, and Schistosoma haematobium. 
These digenetic schistosomes have a complex life-cycle in which free-swimming cercariae emerge from intermediate freshwater snail hosts and infect humans by attaching to the skin via an oral sucker or mucus secretion and penetrate the dermis by releasing proteolytic enzymes. Concurrently, the cercariae shed their tails and transform into schistosomula that enter the venous vascular system where they are carried to the heart and lungs before reaching the systemic circulation. Ultimately, the schistosomula arrive at the liver where they grow into sexually mature adults. Male and female adults form copulating pairs that migrate down the portal vein, eventually reaching the mesenteric or vesical veins, depending on the specific species of schistosome, and begin laying eggs for a period of typically 3 to 5 years. The eggs are generally responsible for triggering the host's immune response that results in the formation of granulomas that lead to the sequelae of clinical manifestations (Bica et al., Infect. Dis. Clin. N. Am. 14: 637–642 (2000); Elliot, Gastroenterol. Clin. N. Am. 25: 599–624 (1996); Morris and Knauer, Sem. Respir. Infect. 12: 159–170 (1997); Schafer and Hale, Curr. Gastroenterol. Reports 3: 293–303 (2001)).
There are limited options available for the chemotherapeutic treatment for Schistosoma infections with the drug-of-choice being the pyrazionoisoquinoline, praziquantel (Elliot, ibid.). Unfortunately, the long-term worldwide application of the drug coupled with the recent discovery of praziquantel-tolerant schistosomes has generated concern over the development of drug-resistant Schistosoma strains (Cioli, Parasitol. Today 14: 418–422 (1998) and Curr. Opin. Infect Dis. 13: 659–663 (2000); William et al., Parasitol. 122: 63–66 (2001)). With few other options available for combating schistosomiasis, there is an urgent need to develop new methodologies for the treatment and prevention of Schistosoma infection (Cioli, ibid.).
Daylily roots (Hemerocallis spp., Hemerocallidaceae) have been used in Asia to treat schistosomiasis (Shiao et al., Acta Pharma. Sinica 9:218–224 (1962); Shiao et al., Acta Pharma. Sinica 9: 217–224 (1962)). However, this method of treatment has been disfavored due to a host of toxic side effects and deaths associated with the administration of Hemerocallis root extracts to humans (Wang et al., Phytochem. 28: 1825–1826 (1989)). Previous efforts to identify the active constituent responsible for the therapeutic properties of Hemerocallis roots lead to isolation of a neurotoxic binaphthalenetetrol known as stypandrol (Wang and Yang, 1993) which had been shown to cause paralysis, blindness and death in mammals (Main et al., Aust. Vet. J. 57: 132–135 (1981); Colegate et al., Aust. J. Chem. 38: 1233–1241 (1985)). In another report by Chen et al. (Acta Pharma. Sinica 9: 579–586 (1962)), researchers obtained a yellow powdery isolate to which the authors ascribed both the biological activity against schistosomes, as well as, the toxic side effects associated with the use of Hemerocallis roots; however, its structure was never identified. While other studies have described additional compounds found in daylilies, none of these efforts have addressed the need to fully characterize the bioactive schistosomicidal chemical constituents from Hemerocallis roots.
Compounds which have antihelminthic activity are known in the prior art such as oxamniquine, metrifonate, and 4-(4-nitroanilino) -phenylisothiocyanate, which are disclosed in U.S. Pat. No. 4,117,156 to Loewe et al. However, oxamniquine is only effective against Schistosoma mansoni, is more active against male rather than female worms, and has little effect on immature worms, and metrifonate is only active against Schistosoma haematobium. U.S. Pat. Nos. 5,091,385, 5,177,073, and 5,489,590 to Gulliya et al. disclose a therapeutic mixture comprising a photoactive compound which is capable of killing tumors, bacteria, viruses, and parasites such as Schistosoma when activated prior to use with an activating agent such as a chemical, radiation (preferably, irradiation with a laser), gamma rays, or electrons from an electropotential device. The photoactive compounds include a general suggestion of anthraquinones.
In light of the above, there remains a need for novel compounds with antihelminthic activity to increase the arsenal of drugs for combating helminthic infections in warm-blooded animals, including humans.